Comparison of the Incidence of Post-intensive Care Syndrome (PICS) Between Elderly and Non-elderly Patients: A Subgroup Analysis of the Japan-PICS Study

Aim: The aging society is expanding, and more elderly patients are admitted to intensive care units (ICUs). Elderly patients may have increased ICU mortality and are thought to have a high incidence of post-intensive care syndrome (PICS). There are few studies of PICS in the elderly. This study hypothesized that the elderly have an increased incidence of PICS compared to the non-elderly. Methods: This is a subgroup analysis of a previous multicenter prospective observational study (Prevalence of post-intensive care syndrome among Japanese intensive care unit patients: The Japan-PICS study) conducted from April 2019 to September 2019. Ninety-six patients were included who were over 18 years old, admitted to the ICU, and expected to require mechanical ventilation for more than 48 hours. Physical component scales (PCS), mental component scales (MCS), and Short-Memory Questionnaire (SMQ) scores of included patients were compared before admission to the ICU and six months later. The diagnosis of PICS required one of the following: (1) the PCS score decreased ≧10 points, (2) the MCS score decreased ≧10 points, or (3) the SMQ score decreased by >40 points. Patients were classified as non-elderly (<65 years old) or elderly (≧65 years old), and the incidence of PICS was compared between these two groups. Results: The non-elderly (N=27) and elderly (N=69) groups had incidences of PICS: 67% and 62% (p=0.69), respectively. Conclusion: There is no statistically significant difference in the incidence of PICS in the non-elderly and elderly.


Introduction
The aging of the world's population requires new considerations for medical care [1].Japan, in particular, has a large proportion of elderly citizens.The percentage of elderly (≧65 years) in Japan reached 28% in 2019 and is projected to rise to 40% by 2060 [2].There are diseases specifically associated with increased age as well as decreased physical function that must be considered in this patient population [3,4].With an increase in the number of the aged in society, the percentage of elderly patients requiring acute care inevitably rises [5], and the admission rate of the elderly to intensive care units (ICUs) also rises [6].
Attention has recently been focused on the long-term well-being and quality of life of patients after discharge from intensive care [7].Post-intensive care syndrome (PICS) is recognized as a condition that continues to impair physical, cognitive, and mental functioning after discharge from the ICU [8].The incidence of PICS was reported to be 63.5% in a multicenter prospective observational study conducted in Japan [9] with a similar incidence of 50-70% reported in the United States [10].A variety of factors have been cited as risk factors for the development of PICS, one of which is age [11][12][13][14].
In Japan, where the aging society is growing rapidly, it has been suggested that elderly patients admitted to the ICU have a higher incidence of PICS compared to the non-elderly.However, to the best of our knowledge, no studies have verified this hypothesis.We conducted a subgroup analysis of the Japan-PICS (J-PICS) study to investigate the incidence of PICS in elderly patients who survived to discharge from the ICU and compared it with non-elderly adults.The ABCDEF bundle is a bundle devised for the prevention of PICS [15] and includes assessment, prevention, and management of pain; both spontaneous awakening trials (SATs) and spontaneous breathing trials (SBTs); choice of sedation/analgesia; delirium monitoring and management; early mobility and exercise; and family engagement and empowerment.This tool has been shown to improve mortality, duration of ventilation, and duration of delirium and coma-free status by increasing compliance with a management bundle [16,17].ABCDEF bundle compliance was calculated as the mean value over three days (Appendix 3).When patients had contraindications for each bundle compliance and did not meet the criteria for each bundle, compliance with each bundle was regarded as having been met.

Design and study setting
Follow-up was conducted for six months following ICU admission, and mortality (ICU, hospital, six months), ICU and hospital length of stay, duration of mechanical ventilation, occurrence of delirium, and disposition status (discharge to home or not) were investigated.Physical, mental, and cognitive functions were compared before and six months after ICU admission using SF-36 and Short-Memory Questionnaire (SMQ).SF-36 consists of the physical component scale (PCS), an assessment of physical functioning, and the mental component scale (MCS), an assessment of mental functioning, each rated with a full score of 100 points, with higher values judged to be better.Cognitive functions were evaluated using SMQ.The SMQ is also in the form of a questionnaire with 12 questions to answer, and scores range from 4 to 46, with scores below 40 considered cognitive impairment.These questionnaires were completed by the patient's healthcare decision-making proxy and were scored at ICU admission and six months after ICU admission, respectively, and the scores were compared.Questionnaires at six months were mailed to patients' homes.

Interventions and comparisons
Patients enrolled in the J-PICS study were divided into two groups, elderly (≧65 years) and non-elderly (<65 years), and compared in terms of PICS incidence, pre-admission baseline, ICU length of stay, hospital length of stay, duration of ventilatory support, ABCDEF bundle compliance, delirium incidence, and rate of discharge to home.
PICS was defined as fulfillment of any of the following (1) to (3) items in a survey conducted six months after ICU admission: (1) if the PCS declines by 10 points or more, (2) if the MCS declines by 10 points or more, or (3) if the SMQ declines and is less than 40 points.

Statistical analysis
Univariate analysis was performed using the Wilcoxon rank-sum test for continuous variables, and the chisquared test or Fisher's exact test was used for categorical variables, if the number in a category was less than 10.Multivariate logistic regression model was used to identify factors associated with the occurrence of PICS.Multivariate analysis included the following variables as confounding factors: age≧65, ABCDEF bundle, education level, and CFS.Statistical significance was set at P<0.05.Statistical analyses were performed using JMPR 13.0.0(SAS Institute Inc., Cary, NC, USA).

Results
A total of 192 patients were included in the J-PICS study, of whom 96 were ultimately followed up (Figure 1).

FIGURE 1: Flowchart of included patients
One hundred and ninety-two patients were included in the J-PICS study, and 96 underwent follow-up.Of these 96 patients, 69 were elderly (≧65 years old), and 27 were non-elderly (<65 years old).
Of these 96 patients, 69 were ≥65 years old (elderly), and 27 were <65 years old (non-elderly).Baseline characteristics and management in the ICU were compared between elderly and non-elderly patients (Table 1).Significant differences were observed between the elderly and non-elderly for Charlson comorbidity index, CFS, educational level, employment status, marital status, residential living status, history of treatment with benzodiazepines, primary diagnosis at the time of admission to the ICU, and ABCDEF bundle compliance.Table 2 shows the results of follow-up after discharge from the ICU.There were no significant differences in the incidence of PICS (67% in the non-elderly vs. 62% in the elderly, p=0.69).There were also no significant differences in hospital length of stay (non-elderly 33 (18-61) vs. elderly 34 (20.5-61.5),p=0.56), days of mechanical ventilation (non-elderly 5 (3-13) vs. elderly 5 (3-6.5),p=0.35), and discharge to home rates (nonelderly 51.9% vs. elderly 46.4%, p=0.63).There were no significant differences in mortality (ICU, hospital, or six months, as shown in Appendix 4) between the two groups: ICU mortality (non-elderly 9.6% vs. elderly  The breakdown of PICS impairments was also investigated, and the comparative findings between the elderly and non-elderly are shown in Table 3.There were no significant differences in the breakdown of physical impairment (non-elderly 67% vs. elderly 44%, p=0.We compared the incidence of PICS among the elderly (65 years or older), with subgroups by age, at 75, 80, and 85 years, and there were no significant differences (Appendix 5).

Key finding of this study
Although being elderly has been considered by some to be a risk factor for developing PICS, there is no significant difference in the incidence of PICS between elderly and non-elderly patients in the present study.
To the best of our knowledge, there are no previous reports comparing the incidence of PICS between the elderly and non-elderly.

The lack of a difference in the incidence of PICS in the elderly and nonelderly
Lee et al. discussed two separate factors that contribute to the development of PICS, personal and ICUrelated, in their systematic review [18].They concluded that older age, female gender, and pre-existing psychological conditions as important patient factors and severity, negative ICU experience, and delirium as ICU-related factors have a strong influence on the development of PICS [18].Kawakami et al. reported in the J-PICS study that a lower education level (only mandatory education) was associated with the development of PICS [9].
Risk factors for the development of PICS for elderly and non-elderly patients were compared, focusing on patient background in the present study.No significant differences were found between elderly and nonelderly patients with respect to gender, severity of illness, or delirium.No data were obtained on pre-existing psychological conditions or negative ICU experiences in the present study.With regard to education, the elderly group has a higher proportion of people at a lower education level (only mandatory education; period of education with less than nine years).Thus, patient background with regard to risk factors for the development of PICS was compared between elderly and non-elderly patients, and there are no differences in risk factors for developing PICS in non-elderly patients.Lee et al. emphasized that patient factors cannot be changed by medical interventions, but ICU-related factors (especially negative ICU experiences and delirium) can be changed by interventions [18].Examining compliance with the ABCDEF bundle, which is designed to prevent PICS [15], the data shows that the level of compliance with the ABCDEF bundle is significantly higher in the elderly group.This effect may have been influenced by ICU staff having the impression that the elderly have a greater risk of developing PICS.ICU staff may have been more diligent in performing the ABCDEF bundle in the elderly, so the PICS incidence may have been lower in the elderly than it might have otherwise been.In fact, the incidence of delirium was not significantly different between elderly and non-elderly patients.It is also reasonable to suggest that a higher ABCDEF bundle compliance rate reduces negative ICU experiences.However, these are only speculations, since multivariate analysis in our study did not suggest a causal relationship between ABCDEF bundle compliance and incidence of PICS.Since the incidence of PICS is not significantly different between the elderly and the non-elderly in the present study, it may be important that dementia is an exclusion criterion for this study.Since, in general, the incidence of dementia is higher in the elderly, it is possible that excluding patients with dementia in the present study may have affected the incidence of PICS in the elderly group.
Focusing on the population included in this study, the elderly group was relatively healthy with a median CFS of 3 and a median BMI of 22.4.CFS is suitable for assessing a patient's baseline frailty and is a score from 1 to 9, with higher scores indicating poorer physical function [19].This may partially explain why mortality and the incidence of PICS did not differ between elderly and non-elderly in the present study.
Focusing on the age of the elderly included in the present study, the median age was 78 (72.5-82).A review of previous studies investigating long-term functional prognosis in the elderly showed that many included elderly were over 80 years old [20].The relatively young age of the elderly included in the present study may also be a reason for the lack of a difference in the incidence of PICS between the elderly and the non-elderly.

PICS in the elderly
Although this study focused on the incidence of PICS in the elderly and non-elderly, attention should also be paid to the incidence of PICS among the elderly including stratification by age groups.In developed countries, the number of very elderly admitted to the ICU is increasing [6].Therefore, it is necessary to subdivide the elderly further by age group and compare the incidence of PICS.Past studies have evaluated ADL changes among elderly who were discharged alive from the ICU [21].Chelluri et al. investigated mortality and ADLs one year after ICU discharge among the elderly (≥65) and compared them to 65-74-yearold patients (N=43) and patients aged ≥75 years (N=54) and found no significant differences [21].We also investigated whether there were differences in the incidence of PICS among the elderly (Appendix 5) but found no significant differences in the incidence of PICS, similar to previous studies.

Strengths and limitations
The present study has acknowledged strengths.First, this is a multicenter study.Second, all items that contribute to PICS in the elderly were evaluated.Existing studies have focused only on individual items related to PICS, such as ADLs and cognitive function [22][23][24][25].The present study is epidemiologically novel because it evaluates each of the three items (physical function, mental function, and cognitive function) as defined in PICS and compares them using quantitative scores before admission to the ICU with evaluations six months after admission.Third, the incidence of PICS is compared between elderly and non-elderly patients.To the best of our knowledge, no previous study has compared the incidence of PICS between the elderly and non-elderly, contributing to the novelty of the present study.
The present study also has acknowledged limitations.First, there is age bias in the patient group.The median age of the elderly included in this study is 77 years, and there were very few patients over 80 years old, which has been more extensively included in previous studies [23,25], which may have affected the results.Second, there are differences in the ability of patients to perform ADLs among the patient groups in the present study.Elderly patients showed a median pre-admission CFS of 3 and a median BMI of 22.4, suggesting that patients in this study had a relatively good ability to perform ADLs and good nutritional status.These factors may have affected mortality and the incidence of PICS.Third, there is a wide range of 95% confidence intervals for odds ratios of PICS incidence between elderly and non-elderly patients (OR 0.83; 95% CI 0.32-2.10).A larger sample size could have produced different results.Finally, the follow-up period is relatively short at six months.Some reports have longer follow-ups, such as one year after ICU discharge [22][23][24][25].If followed for one year after ICU admission, both mortality and PICS incidence would likely have been higher among the elderly.This may have contributed to the difference in the incidence of PICS in the elderly and non-elderly.

Conclusions
Older age is generally considered a risk factor for the development of PICS.However, in this subgroup analysis of data from the J-PICS study, there is no significant difference in the incidence of PICS in nonelderly and elderly patients.To the best of our knowledge, there are no previous reports comparing the incidence of PICS between the elderly and non-elderly.
In this study, included elderly were relatively healthy (median CFS of 3 and a median BMI of 22.4), and ABCDEF bundle (which is designed to prevent PICS) compliance in the elderly is higher than the non-elderly.These factors could have influenced the outcome.

Appendix 1 FIGURE 2 : 2 FIGURE 3 :
FIGURE 2: A schema of the Japan-PICS study PICS: post-intensive care syndrome; ICU: intensive care unit; SMQ: Short-Memory Questionnaire study did not involve animal subjects or tissue.Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work.Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work.Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.

TABLE 2 : Outcomes for patients age<65 and age≧65
PICS: post-intensive care syndrome

TABLE 3 : Impairments of non-elderly and elderly patients
With PICS onset as the outcome, multivariate analysis was performed, and the results are shown in Table4.Being elderly (age ≧65) was not associated with the incidence of PICS (OR: 1.51 (95% CI 0.53-4.26)).

TABLE 4 : Multivariate logistic regression analysis for PICS
PICS: post-intensive care syndrome

TABLE 6 : Comparison of patients aged <65 and aged ≧65 Data
are presented as median (interquartile range) or number (percentage).a: missed nine patients, b: missed 21 patients, c: missed 30 patients BMI: body mass index; APACHE: Acute Physiology and Chronic Health Evaluation; SOFA: Sequential Organ Failure Assessment; ICU: intensive care unit; ARDS: acute respiratory distress syndrome; ECMO: extracorporeal membrane oxygenation; IABP: intra-aortic balloon pump; PICS: post-intensive care syndrome